Process Wednesday: trifluoromethylation on kilogram scale

From this week's C&EN, a great article by Stephen Ritter on process chemistry*, including some really enjoyable coverage of this Boehringer Ingelheim work: 

In one presentation in Orlando, Jason A. Mulder of Boehringer Ingelheim described the challenge of scaling up the fluorination of a versatile synthetic intermediate that his company is using to make a family of new anti-infective drug candidates... 

...Mulder’s target was synthesizing methyl 6-chloro-5-(trifluoromethyl)nicotinate on a 100-kg scale at a reasonable cost. At first, Mulder and his colleagues considered buying and modifying a trifluoromethylated precursor. But the one they needed cost about $800 per kg on a 100-kg scale, which was too much, he said. The team then turned to finding a method to make the fluorinated nicotinate from scratch (Org. Process Res. Dev. 2013, 10.1021/op400061w). 

...The researchers continued their search and zeroed in on methyl chlorodifluoroacetate (MCDFA). Although the compound would take some massaging to serve as a trifluoromethylating reagent, at $12 per mol on a 100-kg scale, the price was right...

...Copper stabilized by the ligand facilitates formation of difluoromethyl carbene, which couples with fluoride ion added to the reaction to form CF₃ ions. The ligand-stabilized copper then coordinates to the heteroaryl ring to displace iodide and transfer CF₃ to the ring. The reaction worked with good yield but not without a couple of monkey wrenches thrown in. 

For one thing, the team couldn’t achieve a catalytic process on the scale they needed because of competing impurity formation—the larger the reaction, the lower the yield. Running reactions that involve CF₃ ion can be problematic because of side reactions of difluoromethyl carbene, Mulder said. The major impurities in this case were by-products with an unwanted fluoroalkyl side chain. 

During the reaction, the CF₂ carbene likely generates multiple fluorinated alkyl copper species that compete with CuCF₃ and react with the iodide, Mulder explained. This radical addition, or telo­merization, is how fluorinated polymers such as polytetrafluoroethylene are made. The team actually could see formed polymer floating in the reaction vessel. 

To curb carbene formation and telomerization, the researchers had to use just the right amount of copper and fluoride ion. But after running hundreds of reactions using the catalytic route with modified conditions, none of the options proved to be optimal. Although the catalytic process was preferred for its lower copper cost and reduced burden of removing copper salts at the end of the reaction, the team opted to simply use a stoichiometric amount of copper, which cut down on carbene formation and reduced the impurities. 

“Our final result was a safe, efficient, scalable process with low impurities that was successfully integrated into the scaled-up synthesis of new drug candidates with an overall cost reduction of 10%,” Mulder concluded. He reiterated that although many trifluoromethylation procedures are available, “finding one that works well on a large scale and at low cost remains a challenge.”

Here's how Mulder and coworkers described the polymer formation in their OPRD paper:

Notably, some solids, which appeared to be highly fluorinated polymeric compounds, were observed floating in the crude reaction mixture. This observation helped explain why a minimum of 3 equiv of MDCFA was required for this reaction. These polymeric byproducts were observed to a small extent on lab scale but had minimal impact. However, during the kilo-lab scale-up of the catalytic trifluoromethylation (Table 3, entry 1), these insoluble polymeric impurities made the workup tedious by complicating phase separations and by causing foaming during the reaction and distillation steps.... 

...Despite great effort, these impurities could not be sufficiently suppressed. Being very similar to the desired product in structure and physical characteristics, these impurities were also very difficult to remove by crystallization at this process stage and downstream. Because of these issues, the stoichiometric copper conditions were pursued for scale-up...

What a neat piece of work! Pretty cool.

*Definitely click on the link for a worthwhile explanation of the ICH classification system for solvents for use in process chemistry, too.